Phenytoin
Stanley R. Resor, Henn Kutt in The Medical Treatment of Epilepsy, 2020
The main advantages of PHT in the treatment of status epilepticus are its effectiveness in controlling convulsions, relatively long half-life, and lack of significant central nervous system depression. Disadvantages are its cardiovascular toxicity if given too rapidly, the time required for giving the full loading dose, and its relative ineffectiveness in suppressing focal epileptic activity. Phenytoin is effective in suppressing experimental seizures as soon as adequate brain concentrations are attained, which, in rats, is only a few minutes. The parenteral form of PHT was developed in the 1950s originally for intramuscular (i.m.) use. Ironically, it is poorly absorbed by this route because it crystallizes in muscle and should not be given i.m. The currently available preparation contains propylene glycol and ethanol. Propylene glycol itself is cardiotoxic (44). The PHT preparation currently available in the United States may be diluted to 5 mg/ml or less in normal saline solution (45). This permits steady administration by infusion equipment. Injection of a bolus of undiluted PHT by hand can be dangerous. Blood pressure and EKG should be monitored during PHT infusion. To overcome these problems with the current preparation, a disodium phosphate ester of phenytoin has been developed. It is water soluble and has an excellent safety profile given i.v. or i.m. (46). If a person’s seizures do not respond to PHT infusion, there is a very high probability that a significant acute CNS insult has occurred. PHT infusion may thus aid in diagnosis.
Overview of the Biotransformation of Antiepileptic Drugs
Carl L. Faingold, Gerhard H. Fromm in Drugs for Control of Epilepsy:, 2019
Phenytoin is an active anticonvulsant drug and is effective for the treatment of seizures without biotransformation. Phenytoin is inactivated primarily by p-hydroxylation on one of the phenol groups attached to the 5 carbon. Oxidative enzymes in the liver promote the formation an arene oxide (epoxide) intermediate which rearranges nonenzymatically to form para- and meta-hydroxy metabolites. Quantitatively, the para-hydroxy metabolite accounts for as much as 90% of an administered dose of phenytoin, with only insignificant amounts of the meta derivative being formed. A very small amount of the arene oxide intermediate is hydrated by epoxide hydrolase to form a dihydrodiol that is further oxidized to a catechol, which is, in turn, methylated to form 3-O-methylcatechol. The arene oxide has not been isolated in humans. The hydantoin ring can be hydrolyzed to form trace amounts of di-phenylhydantoic acid. A dihydroxy metabolite, 5,5-bis (4-hydroxyphenyl) hydantoin, has been reported. The hydroxylated metabolites are conjugated with glucuronic acid and are excreted in urine. The O-glucuronidated metabolites are secreted into bile, but almost all of the conjugated drug is hydrolyzed in the gut and returned to the systemic circulation; little is eliminated in the feces. None of the biotransformation products of phenytoin have any significant antiepileptic activity.
ISQ – Pharmacology
Bhaskar Punukollu, Michael Phelan, Anish Unadkat in MRCPsych Part 1 In a Box, 2019
Side-effects of Phenytoin include: CNS – Drowsiness, ataxia, memory problems, dysarthria, confusion, tremorGI – Gingival hyperplasia, diarrhoea, constipation, nausea, vomiting, liver damage.Haematological – Agranulocytosis, aplastic anaemia, haemolytic anaemia, leucocytosis, monocytosis, anaemia.Dermatological – Measles-like rash, scarlatiniform, maculopapular and urticarial rashes. Rarely: drug-induced lupus, Stevens-Johnson syndrome and toxic epidermal necrolysis.Ophthalmic – Diplopia, nystagmus, conjunctivitis.
Managing pregnancy in women with Sturge-Weber syndrome: case report and review of the literature
Published in Journal of Obstetrics and Gynaecology, 2022
Vignesh Durai, Haritha Sagili, Jayalakshmi Durairaj, Ramesh Ananthakrishnan, Pradeep P. Nair, Arun Keepanasseril, Anish Keepanasseril
A 22-year-old primigravida, diagnosed with SWS since 5 years of age, was admitted at 28 weeks of gestation with recurrent focal seizures. At admission, she had moderate pallor, PWS on the face (right side), and pyogenic granuloma over the scalp’s frontal area (right side). Her haemoglobin level was 9.4 gm/dL, and a deranged GTT (Fasting-95 mg/dL, 1st h-149 mg/dL and 2nd h-160 mg/dL). She discontinued Phenytoin and Valproate, on her own, at four months of pregnancy. After restarting on Phenytoin, she remained seizure-free but required a switch over to Levetiracetam (1 g BD) as she had developed bleeding from gum hyperplasia. Magnetic resonance imaging (MRI) brain was suggestive of SWS (Figure 1(a,b)). She was started on Iron tablets and diabetic diet with which her sugars were well controlled. Her body mass index was 23.4 kg/m2, with gestational weight gain for 9 kg. Her blood pressure with the normal limits and proteinuria was absent. Obstetric ultrasound at 32 weeks gestation diagnosed small for gestational age, with normal doppler. She was followed up with ultrasound surveillance with biometry and doppler sonography. Following the spontaneous onset of labour at 38 weeks, she delivered vaginally, a live male baby weighing 2.35 kg (5th centile of birth weight for gestational age based on Indian academy of Paediatrics growth chart). Puerperium was uneventful. On follow-up, mother is seizure free on antiseizure medications (levetiracetam 1 g BD and phenytoin 100 mg 1TID) and the baby is healthy without any malformations.
Phenytoin and damage to the cerebellum – a systematic review of published cases
Published in Expert Opinion on Drug Safety, 2022
Robin Ferner, Rachael Day, Sally M Bradberry
Phenytoin (diphenylhydantoin, Dilantin®) was introduced into clinical practice as an antiseizure medication (anti-epileptic drug, anticonvulsant) by Merritt and Putnam in 1938 [1]. A review of 329 patients in 1939 supported ‘the strong anticonvulsant properties and marked toxic effects of this drug,’ for by that time, the adverse effects of ataxia, nystagmus, tremor, dizziness, and visual and psychological disturbance had been observed in treated patients [2]. By the 1960s, the adverse effects had been correlated with serum concentrations of phenytoin: ‘nystagmus appearing at approximately 20 [mg/L], ataxia at about 25–30 [mg/L], and disorientation and somnolence at greater than 35 [mg/L].’ [3] The ataxia, nystagmus, and tremor are characteristic of cerebellar dysfunction. Phenytoin has non-linear pharmacokinetics, and this makes dosage adjustment difficult. A small increase in dose can result in an unexpectedly large increase in plasma concentration, and consequent phenytoin toxicity. In most cases, cerebellar signs disappear when phenytoin treatment is stopped, or the dosage is reduced.
Clinical considerations for rapid administration of undiluted or minimally diluted levetiracetam bolus doses
Published in Expert Review of Neurotherapeutics, 2022
Justin P. Reinert, Loulwa Maktabi, Donald Branam, Mercedes Snyder
An open label, multicenter RCT was conducted by Dalziel et al. in 2019 to determine whether IV LEV or phenytoin was the superior second-line medication option in children for convulsive SE [11]. Patients between the ages of 3–16 years of age who had failed initial treatment with benzodiazepine were included in the trial. Two hundred and thirty-three patient encounters were described in the trial, with 119 being randomized to the LEV arm. Patients who received LEV were given a 40 mg/kg bolus dose over 5 minutes, whereas the phenytoin cohort received 20 mg/kg over 20 minutes. While not statistically significant, a greater number of patients in the phenytoin cohort had a cessation of seizure activity within 5 minutes of drug infusion than with LEV (60% vs. 50%, p = 0.16). Patients who received LEV were more likely to be intubated and had a longer intensive care unit and hospital admission, but no significant adverse drug effects or infusion reactions were noted to be exclusive to the LEV cohort [11].
Related Knowledge Centers
- Absence Seizure
- Arrhythmia
- Fosphenytoin
- Benzodiazepine
- Hypertrichosis
- Status Epilepticus
- Anticonvulsant
- Generalized Tonic–Clonic Seizure
- Focal Seizure
- Intravenous Therapy